Processing of damaged DNA ends for double-strand break repair in mammalian cells.
Processing of damaged DNA ends for double-strand break repair in mammalian cells.
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DOI：
10.5402/2012/345805
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发表时间：
2012
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影响因子：
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通讯作者：
Povirk LF
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作者：
Povirk LF
在自然环境中形成的大多数DNA双链断裂（DSB）在末端或末端附近具有化学修饰，其排除直接重新连接，并且需要去除或其他处理，以便重新连接可以进行。自由基介导的DSB通常带有不可连接的3′-磷酸或3′-磷酸乙醇酸末端，并且通常在断裂附近具有氧化的碱基和/或脱碱基位点。拓扑异构酶介导的DSB被拓扑异构酶的共价结合的肽片段阻断。能够解析受损末端的酶包括多核苷酸激酶/磷酸酶，其恢复缺失的5′-磷酸并去除3′-磷酸;酪氨酰-DNA磷酸二酯酶I和II（TDP 1和TDP 2），其分别去除拓扑异构酶I和II的肽片段;以及Artemis和Metnase内切核酸酶，其可以修剪不同结构的受损突出端。TDP 1和APE 1可以去除3′-磷酸乙醇酸和其他3′阻断剂，而CtIP似乎为拓扑异构酶II片段去除提供了替代途径。Ku是一个核心的DSB连接蛋白，可以切割DNA末端附近的脱碱基位点。修补和结扎的下游过程可以容忍残余损伤，有时可以在没有完全清除损伤的情况下进行。尽管存在这些冗余的解决途径，但受损的末端似乎是重新连接的重要障碍，并且它们的解决可能是某些DSB修复的限速步骤。
Most DNA double-strand breaks (DSBs) formed in a natural environment have chemical modifications at or near the ends that preclude direct religation and require removal or other processing so that rejoining can proceed. Free radical-mediated DSBs typically bear unligatable 3′-phosphate or 3′-phosphoglycolate termini and often have oxidized bases and/or abasic sites near the break. Topoisomerase-mediated DSBs are blocked by covalently bound peptide fragments of the topoisomerase. Enzymes capable of resolving damaged ends include polynucleotide kinase/phosphatase, which restores missing 5′-phosphates and removes 3′-phosphates; tyrosyl-DNA phosphodiesterases I and II (TDP1 and TDP2), which remove peptide fragments of topoisomerases I and II, respectively; and the Artemis and Metnase endonucleases, which can trim damaged overhangs of diverse structure. TDP1 as well as APE1 can remove 3′-phosphoglycolates and other 3′ blocks, while CtIP appears to provide an alternative pathway for topoisomerase II fragment removal. Ku, a core DSB joining protein, can cleave abasic sites near DNA ends. The downstream processes of patching and ligation are tolerant of residual damage and can sometimes proceed without complete damage removal. Despite these redundant pathways for resolution, damaged ends appear to be a significant barrier to rejoining, and their resolution may be a rate-limiting step in repair of some DSBs.